Thrombosis In Clinical Practice Research Articles

Shear wave elastography for lower extremity deep vein thrombosis

Aim. To evaluate the potential of shear wave elastography to determine the duration of lower extremity deep vein thrombosis, the effectiveness of direct anticoagulation and patient management strategy.Material and methods. Duplex lower extremity vein scanning, supplemented by shear wave elastography with determination of the average, minimum and maximum Young's modulus, was performed in 98 patients with acute, subacute and chronic thrombosis of the iliac and femoral veins on days 1, 3 and 6 of hospitalization. Based on the coefficient of determination (R2) of the median Young's modulus of a venous thrombus at different stages of thrombosis, the significance of its changes was assessed. Diagnostic information content of Young's modulus was calculated by comparing with the histological data of 17 blood clots removed during surgery.Results. As the age of both iliac and femoral vein thrombus increased, the median of the maximum, average and minimum Young's modulus at all stages of thrombosis steadily increased (R2=0,99). The median of the average Young's modulus at the acute stage was determined to be <17 kPa; at the subacute stage — in the range of 17-32 kPa and chronic — >32 kPa. According to shear wave elastography, in patients with acute and subacute stages of thrombosis, by the 6th day of anticoagulant therapy, the thrombus stiffness increased (R2=0,91-0,96), while in the chronic thrombosis group only a tendency to decrease was observed. The diagnostic information value of studying a thrombus using shear wave elastography relative to its histological examination turned out to be sufficient for use in clinical practice. In acute femoral vein thrombosis, the indication for radical treatment was the average Young's modulus ≤8,1 kPa, the minimum Young's modulus ≤1,7 kPa (sensitivity, specificity, positive and negative predictive values varied in the range of 64,3-88,9%); in subacute — ≤23,0 kPa and ≤11,3 kPa, respectively (55,6-100%).Conclusion. The results indicate that the diagnostic information value of shear wave elastography indicators is sufficient to determine the stage of lower extremity deep vein thrombosis in clinical practice.

Long-term use of tinzaparin for the treatment of cancer-associated thrombosis in clinical practice: Insights from the prospective TROPIQUE study.

Real word data on the efficacy and safety of long-term use of tinzaparin for the treatment of cancer-associated thrombosis (CAT) are scarce. We performed a post-hoc analysis of all cancer patients included in the prospective multicenter observational TROPIQUE study who received long-term treatment with tinzaparin for a first venous thromboembolism (VTE) event. We evaluated the patterns of anticoagulant prescription, the adherence to clinical practice guidelines (CPGs) for the treatment of CAT, and the clinical outcomes within a 6-month follow-up. In total, 301 patients were included in this post-hoc analysis. At study entry, their mean age was 64.6±11.9years and 143 (47.5%) patients were men. The most frequent cancer type was gastrointestinal (23.9%), followed by breast (17.9%) and lung (15.3%) cancer. At time of VTE diagnosis, 164 (57.8%) patients had metastatic disease and 245 (81.42%) were receiving chemotherapy. Based on the aggregation of all study pre-defined criteria, tinzaparin prescription was fully compliant with CPGs in 219 (72.8%) patients. The mean effective treatment duration with tinzaparin was 6.07±0.17months. At 6-month follow-up, the cumulative incidence of recurrent VTE was 5.4% (95% CI: 3.2-9.2%) and the cumulative incidence of major bleeding was 5.8% (95% CI: 3.6-9.6%). Clinical outcomes tended to differ across different types of cancer. Death from any cause occurred in 102 (33.9%) patients, mainly related to cancer progression. This post-hoc analysis of TROPIQUE confirms the favorable benefit-risk ratio of tinzaparin for the long-term treatment of CAT.

Use of thrombolytic agents to treat neonatal thrombosis in clinical practice.

Among children, neonates have the highest incidence of thrombosis. Thrombolytic agents are used for the management of life and/or organ-threatening thrombosis. Literature on the efficacy and safety of thrombolytic agents in neonates is limited. We reviewed the evidence on dosing, administration, monitoring and treatment duration of tissue plasminogen activator (tPA), streptokinase and urokinase (URK) in neonates (≤ 28days). A systematic literature search was conducted of current databases from inception until 31 March 2021. The initial search yielded 6881 articles and 18 were retained for review. tPA, streptokinase and URK was utilized in 12, seven and four studies on 115, 51 and 16 patients, respectively. The dose range for tPA, streptokinase and URK was 0.01 -0.6 mg/kg/h, 50-2000 and 1000-0 000 units/kg/h, respectively, and treatment duration ranged from 30 min to 30 days. This is the first study to objectively summarize the efficacy and safety of thrombolytic agents in neonates. Overall, thrombolysis was associated with 87.9% complete or partial thrombus resolution and 7.4% recurrence risk. The bleeding risk associated with thrombolytic agents was 23.1% on pooled analysis, which is higher than other anticoagulants. Larger prospective studies are required to determine effective dosing regimens of these therapeutic drugs and further clarify their efficacy and safety. Blood Coagul Fibrinolysis 33:000-000 Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

How to use low-molecular-weight heparin to treat neonatal thrombosis in clinical practice.

Among children, neonates have the highest incidence of thrombosis due to risk factors such as catheter instrumentation, an evolving coagulation system and congenital heart disease. Low-molecular-weight heparins (LMWHs) are the most commonly used anticoagulants in neonates. Published guidelines delineate dosing and monitoring protocols for LMWH therapy in newborns. However, challenging clinical situations frequently present that warrant healthcare providers to think critically beyond the range of guidelines, and judiciously resolve specific problems. This review describes the use of LMWH in the neonatal population, including practical aspects such as route and site of administration, preparation from concentrated formulations and methods to minimize pain of subcutaneous injection. It is followed by a discussion on dosing, monitoring and outcomes of LMWH therapy in neonates. The risk of recurrence of thrombosis in neonates after LMWH therapy is approximately 3% based on a pooled analysis of studies reporting this outcome over the last 24 years. The article concludes with an overview of the side-effects of LMWH, including the risk of bleeding which is around 4% based on pooled analyses of more than 30 studies.

How to use unfractionated heparin to treat neonatal thrombosis in clinical practice.

Among children, neonates have the highest incidence of thrombosis due to risk factors such as catheter instrumentation, an evolving coagulation system and congenital heart disease. Unfractionated heparin (UFH) is one of the most commonly used anticoagulants in neonates. Published guidelines delineate dosing and monitoring protocols for UFH therapy in newborns. However, challenging clinical situations frequently present that warrants healthcare providers to think critically beyond the range of guidelines, and judiciously resolve specific problems. This review focuses briefly on the epidemiology of neonatal thrombosis and the use of UFH in this population. It is followed by a discussion on dosing of UFH in neonates, limited evidence that forms the basis of published guidelines with justification for a treatment regimen that precludes the use of a heparin loading dose in newborns and monitoring of UFH therapy with currently available tests such as antifactor Xa (anti-Xa) level and activated partial thromboplastin time (APTT). Multiple studies have demonstrated a lack of correlation between anti-Xa levels and APTT as well as between different anti-Xa assays. Many centers world-wide rely only on APTT for monitoring purposes and do not have access to anti-Xa assays. To address these difficulties, we propose two practical algorithms, with and without the use of anti-Xa levels that clinicians can follow when monitoring UFH therapy in neonates. The article concludes with an overview of the side-effects of UFH.

Transformation of multi-component ginkgolide into ginkgolide B by Coprinus comatus.

BackgroundAs the strongest antagonist of the platelet activating factor, ginkgolide B (GB) possesses anti-ischemic, anti-oxidant and anti-convulsant properties, and it is used for the treatment of thrombosis in clinical practice. Till now, GB is usually obtained from extraction of Ginkgo biloba leaves through column chromatography with an extremely low yield and high cost, which can not meet clinical requirement. Therefore, it is urgent to find a new method to prepare GB.ResultsIn the current study, we studied the ability and mechanism to transform multi-component ginkgolide into GB by Coprinus comatus in order to enhance the GB yield. Except for ginkgolide A (GA) and GB, all the other ginkgolides in the extract were transformed by the strain. In the case of culture medium containing 20 g/L glucose, the transformation product was identified as 12% GA and 88% GB by high performance liquid chromatography-Mass spectrometry (HPLC-MS), two stage mass spectrometry (MS/MS) and nuclear magnetic resonance (NMR). Partial GA was also transformed into GB according to the yield (76%) and the content of GA in the raw ginkgolide (28.5%). Glucose was the key factor to transform ginkgolides. When glucose concentration in medium was higher than 40 g/L, all ginkgolides were transformed into the GB. Proteomic analysis showed that C. comatus transformed ginkgolide into GB by producing 5 aldo/keto reductases and catalases, and enhancing the metabolism of glucose, including Embden-Meyerhof pathway (EMP), hexose monophophate pathway (HMP) and tricarboxylic acid (TCA).ConclusionsC. comatus could transform ginkgolides into GB when the medium contained 40 g/L glucose. When the strain transformed ginkgolides, the glucose metabolism was enhanced and the strain synthesized more aldo/keto reductases and catalases. Our current study laid the groundwork for industrial production of GB.

Simultaneous measurement of thrombin and plasmin generation to assess the interplay between coagulation and fibrinolysis

Normal haemostasis is maintained by a controlled balance between coagulation and fibrinolysis, involving thrombin and plasmin the respective key enzymes. Simultaneous evaluation of both enzymes facilitates, therefore, an overall understanding of normal and pathological haemostasis. Combined thrombin and plasmin generation (T/P-G) assays have been recently described, and we have adapted the technique to investigate the interplay between coagulation and fibrinolysis in patients with various haemostatic disorders. Our modified T/P-G was initiated by the addition of a mixture of optimised lower concentrations of tissue factor and tissue-type plasminogen activator. Thrombin generation (TG) and plasmin generation (PG) were monitored simultaneously using individual fluorescent substrates in separate microtitre wells. The relationship between coagulation and fibrinolysis was demonstrated by analysing the effects of thrombin inhibitors, activated protein C and thrombomodulin. The most evident impairments in TG were observed with plasma samples deficient of coagulation factors participating in the prothrombinase complex. Defects in PG were observed with deficiencies of factor (F)V, FX, fibrinogen, and plasminogen. TG appeared to be a prerequisite for the initiation of PG, and overall PG was governed by fibrinogen concentration. TG in patients with haemophilia A correlated with levels of FVIII activity, but there was no significant relationship between PG and FVIII:C, confirming that the abnormal haemostasis in haemophilia A results in a severe imbalance between coagulation and fibrinolysis. The findings demonstrate that global haemostasis depends on a sensitive balance between coagulation and fibrinolysis, and that the modified T/P-G assay could provide an enhanced understanding of haemorrhage and thrombosis in clinical practice.

Contemporary occurrence of stent thrombosis in clinical practice: Better never than late

Contemporary occurrence of stent thrombosis in clinical practice: Better never than late

Thrombosis of Second-Generation Drug-Eluting Stents in Real Practice: Results From the Multicenter Spanish Registry ESTROFA-2 (Estudio Español Sobre Trombosis de Stents Farmacoactivos de Segunda Generacion-2)

This study sought to evaluate second-generation drug-eluting stent (DES) thrombosis in clinical practice. First-generation DES are associated with a significant incidence of late thrombosis. There is paucity of data regarding real practice late thrombosis incidence and predictors with second-generation DES, zotarolimus-eluting stent (ZES), and everolimus-eluting stents (EES). A prospective, large-scale, non-industry-linked multicenter registry was designed. Complete clinical-procedural data and systematic follow-up of all patients treated with these stents was reported in a dedicated registry supported by the Spanish Working Group on Interventional Cardiology. From 2005 to 2008, 4,768 patients were included in 34 centers: 2,549 treated with ZES, and 2,219 with EES. The cumulative incidence of definite/probable thrombosis for ZES was 1.3% at 1 year and 1.7% at 2 years and for EES 1.4% at 1 year and 1.7% at 2 years (p = 0.8). The increment of definite thrombosis between the first and second year was 0.2% and 0.25%, respectively. In a propensity score analysis, the incidence remained very similar. Ejection fraction (adjusted hazard ratio [HR]: 0.97; 95% confidence interval [CI]: 0.95 to -0.99; p = 0.008), stent diameter (adjusted HR: 0.37; 95% CI: 0.17to 0.81; p = 0.01) and bifurcations (adjusted HR: 2.1; 95% CI: 1.14 to 3.7; p = 0.02) emerged as independent predictors of thrombosis. In the subgroup of patients with bifurcations, the use of ZES was independently associated with a higher thrombosis rate (adjusted HR: 4; 95% CI: 1.1 to 13; p = 0.03). In a real practice setting, the incidence of thrombosis at 2 years with ZES and EES was low and quite similar. The incidence of very late thrombosis resulted lower than was reported in registries of first-generation DES. In the subset of bifurcations, the use of ZES significantly increased the risk of thrombosis.

The risk of definitive stent thrombosis is increased after “off-label” stent implantation irrespective of drug-eluting stent or bare-metal stent use

A limitation of drug-eluting stent (DES) use to FDA-approved indications has been suggested to reduce the risk of stent thrombosis. This study evaluated predictors of stent thrombosis in clinical practice after the use of drug-eluting as well as bare-metal stents (BMS), including adherence to the FDA indications for DES. Between July 2002 and October 2006 percutaneous coronary intervention (PCI) was performed on 5,945 patients using BMS (68%) or DES (32%). Patients had 1-year follow-up for definitive stent thrombosis (ARC criteria). 76 patients (1.27%) developed definitive stent thrombosis. Clinical, procedural, and angiographic parameters were related to those of 786 patients without stent thrombosis to define predictors of stent thrombosis. Off-label or on-label implantation of stents according to the FDA-approved indications for DES was included as parameter in the analysis. In 434 patients, stent implantation was performed within FDA-approved indications and in 428 patients outside of FDA-approved indications for DES. Predictors of stent thrombosis were PCI in acute myocardial infarction (OR = 4.51, P < 0.001), treatment of bifurcation lesions (OR = 4.43, P < 0.001), stent length per mm (OR = 1.07, P < 0.001), implantation of multiple stents (OR = 3.67, P < 0.001), and stent implantation outside of FDA indications (OR = 6.13, P < 0.001). The risk was increased for DES as well as BMS. In a multivariate analysis, PCI in acute myocardial infarction (OR = 2.56, P = 0.014), LV-EF < 30% (OR = 3.60, P < 0.001), treatment of bifurcation lesion (OR = 3.65, P = 0.004), stent length in mm (OR = 1.04, P = 0.015), and implantation of multiple stents (OR = 2.64, P = 0.002) remained predictors of stent thrombosis. Off-label stent implantation was no independent additional predictor as it is a combined parameter of the above-mentioned predictors. Implantation of coronary stents outside of the FDA-approved indications for DES is associated with an increased risk of stent thrombosis using DES and BMS.

Antiplatelet Therapy After Implantation of Drug-Eluting Stents: Duration, Resistance, Alternatives, and Management of Surgical Patients

The routine off-label use of drug-eluting stents (DESs) has been associated with a higher prevalence of stent thrombosis in clinical practice than was suggested in US Food and Drug Administration (FDA) preapproval studies. Consequently, the early identification of patients at risk for stent thrombosis has become a major goal in cardiology. Although a number of factors may be involved in DES thrombosis, the biologic cascade begins with local platelet activation and culminates in platelet aggregation, the generation of coagulation factors, the formation of a fibrin network, and the creation of a stable occlusive thrombus. Current data show that the premature discontinuation of dual-antiplatelet therapy is an important risk factor for DES thrombosis, but the occurrence of stent thrombosis in patients adhering to this drug regimen suggests that some patients are nonresponsive to clopidogrel therapy, primarily because of functional and genetic variability in the cytochrome P450 enzymes. Patients with high platelet reactivity to adenosine diphosphate (ADP) during dual-antiplatelet therapy may be at increased risk for adverse ischemic events, including stent thrombosis. Using a point-of-service assay, Price et al measured platelet function in patients treated with DESs and demonstrated that 75% of patients who developed stent thrombosis were in the lowest quartile of platelet inhibition and the highest quartile of platelet reactivity. Data from the authors' center suggest that there may be a threshold of platelet reactivity, as measured by light-transmittance aggregometry after ADP stimulation, that predicts an increased risk for stent thrombosis. Large prospective studies designed to identify which patients are at risk for stent thrombosis on the basis of platelet function testing are under way and may eventually lead to personalized antithrombotic therapy.

Application of Upper Extremity Radionuclide Venography as a Diagnostic Approach for Port-A Catheter Thrombosis

To investigate the role of upper extremity radionuclide venography as a potential diagnostic modality in the assessment of venous thrombosis associated with a Port-A catheter. Fourteen symptomatic patients who had received Port-A catheter implantation were enrolled. A dynamic nuclear medicine flow study was performed with intravenous administration of Technetium-99m macroaggregated albumin to both upper extremities. Imaging patterns of the venous system were categorized as patency, partial obstruction, and total occlusion. The findings of the dynamic images clearly demonstrated clinical problems. Three patients were free of a definite venous flow change. Three patients had partial obstruction of venous return. A significant cut-off of venous return was demonstrated in 8 patients, and total occlusions were hence diagnosed. All patients underwent this procedure smoothly without any complication. These results suggest that upper extremity radionuclide venography is an easily performed and effective method for diagnosing Port-A catheter thrombosis in clinical practice.

Book Review Thrombosis in Clinical Practice Edited by Andrew D. Blann, Gregory Y.H. Lip, and Alexander G.G. Turpie. 326 pp., illustrated. Abingdon, England, Informa Healthcare/Taylor &amp; Francis, 2005. $139.95. 1-84214-163-5

Book Review Thrombosis in Clinical Practice Edited by Andrew D. Blann, Gregory Y.H. Lip, and Alexander G.G. Turpie. 326 pp., illustrated. Abingdon, England, Informa Healthcare/Taylor &amp; Francis, 2005. $139.95. 1-84214-163-5

Thrombosis in Clinical Practice. Edited by: Andrew D Blann, Gregory YH Lip, Alexander GG Turpie.

As mentioned by editors, expectant readers of Thrombosis in Clinical Practice are physicians, general practitioners, nurse practitioners, and healthcare workers. With this in mind I browsed Thrombosis in Clinical Practice. Thrombosis is a fast moving area and is not easy to give updated information of its pathophysiology and treatment in about 300 pages as it was successfully done in this book. This multiauthored text combines basic concepts of mechanisms of thrombosis formation as well as therapeutic approaches. It provides short overviews on risk factors, therapeutics and a systematic discussion of arterial and venous thrombosis management with final recommendations according to authors experience. It successfully delivers concise information on all aspects of a given type of thrombosis for physicians and nurses who care for patients with thrombosis related diseases. The first five chapters review mechanism of thrombus formation (although importance of inflammation was omitted in Chapter 1), role of hemostatic system in arterial and venous thrombosis, characteristics of what authors call commonly used anticoagulant and antiplatelet (which include aspirin, heparin, and warfarin starting with an interesting historical perspective of each of them). Without doubt risk of bleeding is most critical aspect of patients under antithrombotic treatment; it happens and what to do are questions answered in Chapter 4. Factors which determine thrombophilia are discussed in Chapter 5. Practical recommendations for screening patients with potential or already developed thrombotic process are noteworthy. The following Chapters 6 to 12 deal with treatment of arterial and venous thrombosis and include management of atrial fibrillation where known, well established therapies are discussed. In cardiac valves, Chapter 7, a comprehensive indication for used of oral anticoagulant with or without aspirin and management of pregnant patients was explained. Since some not so recent data have been included in beginning of this chapter authors missed to mention that in patients with cardiac valves prostheses, first combined therapy (oral anticoagulant plus dipyridamole) for thrombotic preventing treatment was published by Sullivan et al. (N Engl J Med. 1971;284:1391-4), and belongs to our group first report on use of aspirin plus oral anticoagulant (Altman et al. J.Thorac.Cardiov. Surg. 72: 127,1976). Chapters 8 to 11 review benefit and risk of antithrombotic therapy in coronary artery disease, thrombosis prevention after coronary interventions and, an updated discussion on risk factors, pathophysiology, diagnosis and antithrombotic therapy in peripheral arterial disease and ischemic stroke. Chapter 12 deals with an important and still controversial topic: Management of venous thromboembolism during pregnancy. The authors discuss conflictive positions in diagnostic as well as in treatment of deep venous thrombosis in pregnant women. The antithrombotic treatment in women with recurrent miscarriage and thrombophilia which is conflictive and still unresolved is not discussed in this chapter. Chapter 13 was dedicated to thrombophilia. I wonder why it was included at end of book and not among first 5 Chapters. I also wonder why Ian Jennings omits to discuss whether decrease of fibrinolysis is (or not) a potential thrombotic risk factor. Importantly, a chapter on thrombosis in children was incorporated in this book and finally, a chapter on new drugs for anticoagulant therapy, which could be called the after coumadin/heparin era, was also included with updated information on pentasacharides fondaparinux and idraparinux, on drugs affecting factor VII activity, direct Factor Xa and direct thrombin inhibitors. Therapeutic characteristics of antiplatelet drugs is provide in this Chapter. This part of article shows feeble beneficial effect of clopidogrel plus aspirin, in reducing combining risk of ischemic stroke, MI or vascular death compared with aspirin in several artery diseases and likely to be beneficial in patients underwent percutaneous coronary intervention. The antithrombotic capacity of glicoprotein IIb-IIIa (integrin α2b/β3) inhibitors, potential value of von Willebrand factor antibody AJW 200 and thrombolytic therapy are also discussed. This textbook is particularly interesting for general practitioners, medical students and trainees in haematology. It will be useful for physicians in several disciplines. In short: It fulfils its stated purpose.

Enzyme-Controlling Medicines: Introduction

A short history of the research work of S. Okamoto and co-workers, for the previous 50 years, is briefly described. In the 1950s, when the physiologic role of fibrinolysis had not been established, they began to seek for compounds that inhibit the action of plasmin. They examined approximately 200 lysine derivatives and discovered epsilon aminocaproic acid (EACA) and tranexamic acid (t-AMCHA). In the 1970s, we selected thrombin as the target enzyme to be controlled; structure-activity relationship studies, taking arginine as the skeleton structure, led to the discovery of the selective thrombin inhibitor No. 205 (4-ethyl-1-[N2-(5-dimethylamino-1-naphthalenesulfonyl)-L-arginyl]- 1-piperidine), and further attempts to minimize the toxicity finally led to No. 805 (argatroban, MD-805, (2R,4R)-4-methyl-1-(N2-[(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)-sulfo nyl]-L-arginyl)-2-piperidine carboxylic acid). Argatroban, without any cofactor, inhibits thrombin competitively. The high selectivity of the action of argatroban is promising for treating thrombosis in clinical practice. More recently, taking advantage of our knowledge obtained through previous studies, active center-directed plasmin inhibitors and a selective inhibitor of kallikrein have been found.